Virus-targeted therapeutic for EBV-Associated Malignancies

EBV 相关恶性肿瘤的病毒靶向治疗

• 批准号: 9312763
• 负责人: SUSAN Park PERRINE
• 金额: $ 51.96万
• 依托单位: PHOENICIA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312763
• 关键词: Acquired Immunodeficiency Syndrome; Adverse event; African Burkitt' s lymphoma; Animal Model; Antiviral Agents; B-Cell Lymphomas; Breast Carcinoma; Burkitt Lymphoma; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; Data; Databases; Development; Drug Exposure; EBV-associated malignancy; Enzymes; Family; Ganciclovir; Gene Expression; Goals; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Lead; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Malignant lymphoid neoplasm; Measurable; Nasopharynx Carcinoma; Neoplasms; Normal Cell; Oral; Outcome; Outpatients; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Play; Population; Prodrugs; Protein Kinase; Protocols documentation; Radiation; Radiation therapy; Refractory; Regimen; Research Personnel; Resistance; Role; Safety; Site; Small Business Innovation Research Grant; Stomach Carcinoma; System; TK Gene; Therapeutic; Thymidine Kinase; Toxicology; Transplantation; Treatment Protocols; Validation; Viral; Viral Drug Resistance; Viral Genome; Virus; antiviral nucleoside analog; chemotherapy; design; gammaherpesvirus; killings; meetings; member; neoplastic cell; nucleoside analog; oncology; outcome forecast; partial response; pre-clinical; preclinical development; prototype; public health relevance; research clinical testing; response; sarcoma; targeted treatment; therapeutic evaluation; tumor; virus development

 DESCRIPTION (provided by applicant) Epstein-Barr virus (EBV) is associated with a number of human malignancies, and likely plays a causal role in two endemic tumors: African Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC). Clonal EBV can be found in Burkitt's lymphomas, T/NK lymphomas, and post-transplant lymphoproliferative disorders (LPD), as well as some T- and B-cell lymphomas, and half of Hodgkin's lymphomas. In addition, EBV may be involved in the development of other neoplasias, including AIDS-related sarcomas, and gastric carcinomas, and certain breast carcinomas. However, we have demonstrated that merely the very presence of the virus in a tumor provides the opportunity for a targeted therapeutic strategy. EBV persists in these tumors in a dormant or "latent" state. Many Herpes-family virus-infected cells can be killed by nucleoside analog antiviral pro-drugs like ganciclovir, which targe the viral thymidine kinase (TK) enzyme. EBV is resistant to these antiviral agents because latently-infected tumor cells do not express the viral (TK) enzyme. We have demonstrated that selected agents which induce the EBV-TK gene expression in the tumor cells renders the tumor susceptible to standard anti-viral agents. This is a tumor-targeted therapy, in that only the tumor cells (containing EBV) are killed - normal cells are spared. We have conducted a successful Phase I/II study of this virus-targeted therapeutic approach in patients with EBV-associated lymphoid malignancies, all of which were resistant to conventional radiation and chemotherapy. Our targeted therapy produced complete clinical responses (CRs) in 26% of patients, and good partial responses (PRs) in an additional 40% within one treatment cycle (total tumor response rate of 67%). This is an exceptionally high rate of response, and the adverse event profile was favorable. The overall goal of this SBIR proposal is to develop a more potent, more selective, and more patient-accessible virus-targeted therapeutic for testing in EBV+ malignancies. In our Phase I period, we have screened, validated, and selected a highly-potent, clinical-stage lead inducing agent, which is orally-available and has significant human safety data, for use in combination with an anti-viral agent for EBV lymphomas. In this Phase II proposal, we will complete the preclinical development of the virus-inducing agent for this specific indication, generate data to expand its potential therapeutic application and value, and prepare for a Phase II proof-of-concept clinical trial. Our Specific Aims in this Phase II Proposal are: 1.) Optimize lead compound - Refine this EBV/KSHV-targeted therapeutic regimen in animal models; 2.) Expand application of this therapeutic approach into other herpesvirus-associated malignancies; 3.) Complete pre-clinical development; 4.) Clinical trial planning and set-up. Measurable Outcomes and Deliverables: i.) Optimization of treatment regimen; ii.) Validation of this virus-targeted approach in other malignancies associated with γ-herpesviruses; iii.) Complete pre-clinical development of lead compound; iv.) Filing of IND for phase II clinical trial.

 描述（由申请人提供）EB病毒（EBV）与许多人类恶性肿瘤相关，并可能在两种地方性肿瘤中起因果作用：非洲伯基特淋巴瘤（BL）和鼻咽癌（NPC）。在伯基特淋巴瘤、T/NK淋巴瘤和移植后淋巴增生性疾病（LPD）以及一些T细胞和B细胞淋巴瘤和一半的霍奇金淋巴瘤中可以发现克隆性EBV。此外，EBV还可能参与其他肿瘤的发生，包括艾滋病相关的肉瘤、胃癌和某些乳腺癌。然而，我们已经证明，仅仅是肿瘤中病毒的存在就为靶向治疗策略提供了机会。EBV在这些肿瘤中以休眠或“潜伏”状态存在。核苷类似物抗病毒前体药物如更昔洛韦可杀死许多疱疹病毒感染的细胞，其靶向病毒胸苷激酶（TK）。EBV对这些抗病毒剂具有抗性，因为潜伏感染的肿瘤细胞不表达病毒（TK）酶。我们已经证明，所选择的诱导肿瘤细胞中EBV-TK基因表达的药物使肿瘤对标准抗病毒药物敏感。这是一种肿瘤靶向治疗， 细胞（含有EB病毒）被杀死-正常细胞幸免。我们已经在EBV相关淋巴系统恶性肿瘤患者中成功进行了这种病毒靶向治疗方法的I/II期研究，所有这些患者都对常规放疗和化疗有抵抗力。我们的靶向治疗在26%的患者中产生了完全临床反应（CR），在一个治疗周期内另外40%的患者产生了良好的部分反应（PR）（总肿瘤反应率为67%）。这是一个非常高的反应率，不良事件的特征是有利的。该SBIR提案的总体目标是开发一种更有效，更具选择性，更易于患者获得的病毒靶向治疗药物，用于EBV+恶性肿瘤的测试。在我们的I期阶段，我们筛选、验证和选择了一种高效的临床阶段先导诱导剂，该药物可口服，并具有重要的人体安全性数据，可与抗病毒药物联合用于EBV淋巴瘤。在本次II期提案中，我们将完成针对该特定适应症的病毒诱导剂的临床前开发，生成数据以扩展其潜在的治疗应用和价值，并为II期概念验证临床试验做准备。我们在第二阶段建议中的具体目标是：1。优化先导化合物-在动物模型中优化这种EBV/KSHV靶向治疗方案; 2.）将这种治疗方法的应用扩展到其他疱疹病毒相关恶性肿瘤; 3.）完成临床前开发; 4.）临床试验计划和设置。可衡量的结果和可衡量的结果：i.）治疗方案的优化; ii.）在与γ-疱疹病毒相关的其他恶性肿瘤中验证这种病毒靶向方法; iii.）完成先导化合物的临床前开发; iv.）II期临床试验IND备案。